1. Field of the invention
The invention relates to methods of using compositions for forming microbial sealant drapes. In particular, the invention relates to the use of compositions of combinations of cyanoacrylates for the in situ formation of microbial sealant drapes that can be used in surgery to protect patients from surgical site infections.
2. Description of the Prior Art
Surgical site infections (SSIs) can be classified into two categories: (1) incisional and (2) organ, which includes organs and spaces manipulated during an operation. Incisional infections are further divided into superficial infections and deep soft tissue-muscle and fascia infections. The Centers for Disease Control and Prevention estimates that approximately 500,000 surgical site infections occur among an estimated 27 million surgical procedures conducted every year in the United States. Surgical site infections (SSI) are listed as the second most common cause of nosocomial infection after urinary tract infections, which accounts for 40% of hospital-acquired infections among surgical patients. Twenty five to thirty-eight percent of all nosocomial infections among surgical patients are estimated to be incisional surgical site infections. SSI is a significant cause of surgical morbidity and mortality, occurring in 2-5% of patients having clean extra-abdominal operations and up to 20% of patients undergoing intra-abdominal procedures. Patients with SSI are twice as likely to die, 60% more likely to be admitted to an Intensive Care Unit, and more than 5 times more likely to be readmitted to the hospital than patients who are not infected. Surgical site infections result in longer hospitalization and have large economic impact on patients and the health care system. Patients with surgical site infections are hospitalized an additional 7 days on average. The longer hospital stay cost an additional $3,152 on average. The average total cost for medical care during the eight weeks after hospital discharge is $5,155 for patients with surgical site infections compared with $1,773 for patients without SSIs. The total cost includes out patient visits, pharmacy, radiology services, re-hospitalization, skill-nursing facility, home health aids, and durable equipment.
The frequency of surgical site infections in patients varies from surgeon to surgeon, hospital to hospital, surgical procedure to surgical procedure and patient to patient. Surgical site infections can be caused by external sources of contamination including surgical personnel, surgical environment, and surgical instruments. Most SSIs are, however, caused by patient's own normal skin flora which can enter the body through the surgical incision. The patient's skin flora is considered as the first and foremost pathogenic source because the transmission of bacteria from skin to the incision is very efficient. Innocuous bacterial flora on the skin may also be colonized by pathogenic organisms. The bacteria of normal skin flora can cause wound infection in the presence of foreign materials that greatly enhance the pathogenic potential of these bacteria. Therefore, bacterial contamination occurs predominantly during and following surgical procedures.
Different methods of preventing SSIs have been developed to reduce patients' surgical site infections. Advanced surgical techniques and skillful surgeons can reduce the duration of surgery. Operation personnel and operation room hygiene management can lower the probability of exogenous pathogens. Operations that are conducted when patients have healthy physical and psychological states may enhance patients' immune system so that the chance of surgical infections may be considerably reduced. Thoughtful plans and careful selection of effective antibiotics can also help reduce the chance of contamination of bacteria.
Topical bactericidally active or antimicrobial agents such as iodophors, chlorhexidine, and alcohol-containing products have been applied to the surgical site before surgery to kill bacteria. These agents are preoperative skin preparation products, washes, surgical scrub tissues, wound cleaners, lotions and ointments. As early as 1960s, the successful use of prophylactic antibiotics was reported in a randomized, prospective, placebo-controlled clinical study of abdominal operations on the gastrointestinal tract. The success of antibiotic prophylaxis was due to the appropriate patient selection and wise choice of available agents.
U.S. Pat. No. 4,542,012 teaches the application of antimicrobial agents by depositing antimicrobial compositions onto human skin to form an antiseptic film. The antimicrobial composition is applied to the skin as a liquid solution in a fugitive solvent. After the solvent evaporates, a thin film containing antimicrobial agent is formed on the skin.
U.S. Pat. No. 5,916,882 discloses a providone-iodine alcohol gel antimicrobial skin-preparation formulation which is used to disinfect a surgical site. The pre-operative skin-preparation formulation quickly kills bacteria when applied to the surgical site. The skin-preparation formulation continues to effectively inhibit microorganism growth in the applied area for a relatively long period of time. Application of the skin-preparation formulation is controllable because the formulation does not run when applied to a patient. The antimicrobial skin-preparation formula includes iodine, alcohol and gel.
U.S. Pat. No. 6,228,354 provides a skin-preparation composition which does not harm the skin yet promotes asepsis on the skin. The skin-preparation composition disclosed has a rapid antimicrobial activity when in a liquid form and a sustained antimicrobial activity when dry. The skin preparation composition forms a water-resistant film on skin and is not readily removed when a wound or surgical site is sponged or irrigated. The antimicrobial film can be removed by rubbing an aqueous solution having the proper pH onto the skin. This patent describes a film-forming topical antimicrobial composition that includes a broad spectrum antimicrobial agent, a water-resistant polymer system, a neutralizer, a pH sensitive polymer, and an alcohol.
U.S. Pat. No. 6,488,665 discloses an antimicrobial skin-preparation delivery system used to disinfect a surgical site. The antimicrobial skin-preparation formula consists of iodine, alcohol and gel. The delivery system is composed of an antimicrobial alcohol gel formulation contained within a sealed, flexible container and a gel formulation dispenser connected to the container. A porous applicator pad with enlarged holes for passage of the gel formulation is described. The flow rate of the gel formulation is controlled by the external pressure applied to the flexible container.
US Patent Publication Nos. 20040126355 and 20080102053 disclose antimicrobial skin compositions comprised of an antimicrobial agent, water, an alcohol, and one or more pH sensitive viscosity builders. The composition's viscosity is from 100 cp to 1,000 cp and the formulation combines the advantages of an antimicrobial agent and an alcohol. The viscosity of the formulation permits dispensing from the applicator, while preventing the solution from flowing away from the wound area. pH sensitive methacrylic polymers are used as viscosity modifiers. The preparation forms a water-resistant film that is difficult to remove during wound irrigation, but can be easily removed upon completion of the procedure.
One of the disadvantages associated with topical application of skin preparation products is that the antimicrobial agents are only effective for a short period of time. Bacteria that may have survived the initial application of skin preparation products can proliferate and produce a large pathogen population. In addition, appropriate antimicrobial prophylaxis is determined by many factors such as proper case selection, anti-microbial agent selection, dosing and route of administration and duration of therapy. Inappropriate use of antimicrobial agents not only increases the cost of medical health care, but also exposes the patient to potential toxicity and other risks. Moreover, many gram-positive organisms isolated from patients with surgical site infections are resistant to multiple antimicrobial agents. The problem of antimicrobial resistance in gram-positive nosocomial pathogens has been a growing concern.
In addition to the use of antimicrobial skin preparation products, surgical incise drapes have also been used to help reduce the migration of germs and bacteria into the incision site. The surgical incise drape is usually a clear polymeric film with an adhesive backing on one side which is in turn covered with a release liner. Generally, the incise drape is used in conjunction with towels or surgical drapes to maintain the surgical site as sterile and clean as possible in order to inhibit surgical site infections. A continuous or longer lasting antimicrobial effect may be obtained by combining the antimicrobial agent with a surgical incise drape.
U.S. Pat. No. 3,579,628 discloses a hydrophilic acrylic film dressing which contains a composition which reacts with water to generate a bacteriostatic substance. The hydrophilic acrylic films are particularly suitable for use as occlusive dressings and for reducing bacteria.
U.S. Pat. Nos. 4,310,509 and 4,323,557 disclose dermatologically acceptable compositions made of a pressure-sensitive surgical incise drape and a broad-spectrum antimicrobial agent which can be released from the drape placed in contact with the skin. The active broad-spectrum antimicrobial agent is polyvinylpyrrolidone-iodine complex or chlorhexidine. The antimicrobial agents are applied onto the surgical drape which is made of polymeric materials such as polyurethane, polyvinyl ethers, polyesters, or polyethylene.
U.S. Pat. No. 4,340,043 discloses an adhesive-coated incise drape material incorporating uniform amounts of silver sulfadiazine as an antimicrobial agent. The incise drape is made of polyurethane sheets with an adhesive layer.
U.S. Pat. No. 4,643,181 discloses a surgical dressing or incise drape material comprising a substrate coated with an antimicrobial containing adhesive. The substrate may be a woven or knitted fabric, a nonwoven fabric, a plastic or a polymeric film. The preferred substrate in the invention is a polyurethane film. The antimicrobial is polyhexamethylene biguanide hydrochloride, which is distributed in the adhesive as particles with a size in the range of 20 to 300 microns.
U.S. Pat. No. 5,069,907 discloses a synthetic polymeric film or fabric surgical drape having incorporated therein a broad spectrum antimicrobial agent. The drape may have an adhesive layer attached to one of its external surfaces. The preferred antimicrobial agent used is 5-chloro-2-(2,4-dichloro-phenyl)phenol. Suitable adhesives utilized include polyacrylate adhesives.
U.S. Pat. No. 5,803,086 discloses adhesive coated incise drapes useful in surgical procedures. The incise drapes comprise a flexible film backed coating on one side with a dermatologically acceptable pressure sensitive adhesive (PSA) on the other side. The incise drape can be applied by two people wherein one person holds the core and a second person unrolls the drape by pulling on the handle protruding from the opposite end of the drape.
U.S. Pat. Nos. 5,979,450; 5,985,395 and 6,742,522 provide surgical incise drapes comprising a flexible film having a major portion thereof coated with an adhesive. The incise drape has a leading edge and a trailing edge and further includes a film handle at the leading edge. Methods described include providing a drape, grasping the film handle of the drape, pulling upon the liner to remove at least a portion of the liner exposing at least a portion of the adhesive coating the major portion of the flexible film, holding the surgical incise drape in a position such that at least a portion of the adhesive is contacting the patient, and then removing portions of the liner remaining.
US Patent Publication Nos. 20020002223, 20040115274 and 20080078413 disclose adhesive compositions containing acrylic polymers, tackifiers and a broad spectrum antimicrobial agent. The adhesive composition is an essentially solventless composition. The antimicrobial agent utilized is diiodomethyl-p-tolylsulfone with a preferred concentration of antimicrobial agents in the adhesive of about 0.1% to about 2% loading by weight. The antimicrobial adhesive composition is included in a polymeric substrate to form a surgical drape. The polymeric substrate is preferably a polyester or co-polyester sheet material.
US Patent Publication No. 20050284487 discloses a draping product, which is coated with adhesive along at least one edge. The adherence strength of the adhesive is greater than 0.5 N/25 mm when applied to skin. The damage to stratum corneum of the skin covered by the adhesive is less than 30% after removal. The adhesive coating is comprised of a pressure sensitive adhesive such as silicone elastomer, a hydrogel or a soft, tacky hot melt adhesive.
US Patent Publication No. 20070048356 describes an antimicrobial material composition that can be applied to material substrates. The antimicrobial composition includes a first or primary antimicrobial agent, such as polyhexamethylene biguanide (PHMB), a second antimicrobial agent, an anti-static agent or fluoropolymer and/or an organic acid. The substrate may encompass both woven and nonwoven fabrics made from either natural or synthetic fibers, rubber, plastic, and other synthetic polymer materials. The composition exhibits an effective microbe-killing efficacy within a period of about 30 minutes.
In spite of the beneficial properties of conventional surgical drapes with respect to inhibition bacterial infection, there are many challenges and problems associated with the conventional surgical drapes regardless of whether they incorporate antimicrobial agents. Under certain circumstances conventional surgical drapes may actually increase the risk of surgical site infection. Conventional surgical drapes can be lifted during surgery which results in entry of bacteria into the surgical site. The lifting of the conventional surgical drape is usually caused by failure of the adhesive to remain in contact with the patient's skin. Attempts to increase adhesive strength may also prove disadvantageous because more force is then required to remove the drape from skin leading to damage of the skin near the surgical site.
Conventional surgical drapes are normally large and difficult to apply to the patient without wrinkling the drape film. Wrinkling of the surgical drape at the surgical site may block visibility, making it difficult for the surgeon to see the incision site. In addition, the surgical drape will not prevent microorganisms from entering the incision if the drape is wrinkled. Wrinkling is especially problematic with application of the conventional surgical drapes to a non-flat skin surface such as the elbow or knee.
Incorporation of antimicrobial agents into conventional surgical drapes may permit the antimicrobial action of the agents to last longer. Antimicrobial agents currently available are, however, not effective at killing and immobilizing pathogens on the surface to which the agents are applied. The extensive use of antimicrobial products has raised concerns about antimicrobial resistance to antibiotics. In addition, most antimicrobial compounds are heat labile and cannot survive radiation sterilization. This makes it difficult to prepare sterile surgical drapes infused with antimicrobial agents.
Even though many different procedures have been applied to reduce surgical site infections, the risk of such infections still exists because of the continuing survival of skin bacteria after these treatments. Since endogenous flora on patient's skin plays a key role in the development of surgical site infections, a simple and comprehensive solution to the problem would be to minimize endogenous bacteria at and around the surgical site. It is known that cyanoacrylate polymer film can act as a mechanical barrier to penetration by bacteria while maintaining a natural healing environment. Cyanoacrylate monomers, which polymerize on contact with tissue surface to provide a thin and flexible polymer film, have been used as tissue adhesives for several decades. Cyanoacrylate adhesives also exhibit strong bond strength and very rapid cure time.
Cyanoacrylate' properties as adhesives may also make them desirable candidates as microbial sealant drapes. Cyanoacrylate microbial sealant drapes could prevent surgical site infections by overcoming the difficulties experienced by the conventional surgical drapes. U.S. Pat. No. 7,255,874 discloses that modified cyanoacrylate monomers can be used in various medical applications including wound closure, treatment of burns and abrasion and as surgical drapes. U.S. Pat. No. 5,730,994 describes methods for draping a surgical site by the in situ formation of cyanoacrylate polymer drape over skin surface. While the specification describes various cyanoacrylate monomers that can be used as surgical drapes, the preferred compositions contained only n-butyl cyanoacrylate. Furthermore, only n-butyl cyanoacrylate compositions were tested as surgical drapes.
There are several shortcomings associated with using n-butyl cyanoacrylate as a surgical drape. Compared to longer chain alkyl cyanoacrylates, n-butyl cyanoacrylate is less flexible and cracks more easily after forming a polymer film. Thus a plasticizer is usually needed in the n-butyl cyanoacrylate formulation to improve flexibility. In addition, short-chain cyanoacrylates polymerize quickly and then degrade rapidly into formaldehyde and the corresponding alkyl cyanoacetate, which can cause significant histotoxicity. Polymer films of n-butyl cyanoacrylate sloughs off from skin faster than that of long alkyl chain cyanoacrylates. Skin irritation also occurs with the use of n-butyl cyanoacrylate.
Hence, development of a cyanoacrylate-based microbial sealant drape which can immobilize the infectious microorganisms and effectively seal out the bacteria from a surgical site is desired. It is desirable to have a cyanoacrylate-based microbial sealantdrape product that can provide a uniform and flexible film. It is also desirable to develop a cyanoacrylate microbial sealant drape with significantly less tissue toxicity. Additionally, it is also desirable to develop an easy to use cyanoacrylate-based microbial sealant drape that will last a long time after the surgery to inhibit the postoperative surgical site infections.